Studies of cardiac sympathetic nerve function in congestive heart failure indicated that increased sympathetic drive to the failing heart is secondary to both an increase in neuronal release of transmitter and a decrease in the efficiency of transmitter reuptake. Resulting inappropriately increased norepinephrine concentrations in myocardial interstitial fluid may thus contribute to the pathogenesis in heart failure by direct toxic effects of catecholamines on the myocardium and by facilitating cardiac hypertrophy and arrhythmias. Examination of patients at various stages of heart failure revealed that the changes in cardiac sympathetic function (impaired neuronal norepinephrine reuptake and increased cardiac norepinephrine spillover) precede changes elsewhere in the body. Another study showed that impaired exercise capacity in patients with congestive heart failure was associated with reduced responsiveness of cardiac sympathetic nerves to appropriately increase transmitter release. Increased sympathetic drive in heart failure was shown to be normalized after cardiac transplantation. These studies suggest that normalizing the various abnormalities of sympathetic nerve function may provide a strategy for therapeutic interventions designed to halt or reverse the progression of congestive heart failure. The possibility that beta-adrenergic blockers may exert their therapeutic actions in heart failure by normalizing cardiac norepinephrine spillover is being examined by a double blind clinical trial of the effects of beta- adrenergic blockade on cardiac sympathetic nerve function in patients with congestive heart failure. Examination of the effects of angiotensin- converting enzyme inhibitors, administered by intracoronary infusion, showed that this treatment failed to reduce release of norepinephrine from cardiac sympathetic nerves in patients with angina pectoris. Whether such a mechanism may be responsible for the therapeutic actions of angiotensin- converting enzyme inhibitors in the treatment of congestive heart failure remains to be established. Parallel preclinical studies in anesthetized dogs are being carried out in order to develop new methods for more complete and detailed examination of cardiac sympathetic nerve function in our ongoing clinical studies. Other preclinical studies in fetal sheep have shown that birth is associated with a transient increase in heart ventricular norepinephrine release and that this may contribute to regulation of some of the profound hemodynamic adjustments occurring during transition from the fetal to the neonatal environment.